Oral bacteria exist as compositionally and structurally complex populations in biofilms colonizing the tissues of the mouth. In most cases, oral biofilms are compatible with health. It is perturbations caused by environmental stresses that induce the changes in the composition and metabolic activities of biofilm bacteria that lead to the initiation and progression of oral diseases. The overall goals of the proposal are to provide detailed molecular and physiologic information about the capacity of oral bacteria to form and persist in biofilms, with particular focus on environmental stresses that can modulate the virulence of oral bacteria and enhance the pathogenic potential of oral biofilms. To achieve these goals, the following aims are outlined: Aim 1. Analyze the molecular basis for post-transcriptional control of dnaK operon expression and stress tolerance in S. mutans. Aim 2. Determine the role of (p)ppGpp in physiologic homeostasis, growth and survival decisions, and virulence expression in exponentially-growing S. mutans. Aim 3. Dissect the molecular basis for stress tolerance and modulation of relP expression by a MarR transcriptional regulator and two ATP binding cassette exporters. By implementing the research plan, we will disclose fundamental details about the intimate linkage of stress tolerance with the ability of this organism to form biofilms on surfaces of the oral cavity. The research will provide the scientific community with an array of information that can be used to develop novel and more effective strategies to prevent and treat oral diseases and other debilitating human infectious diseases.